Discovery and SAR of novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu(5))

作者：Luz Martin Martin Maria; Manuel Bartolome Nebreda Jose; Conde Ceide Susana; Alonso de Diego Sergio A; Lopez Silvia; Martinez Viturro Carlos M; Han Min Tong; Lavreysen Hilde; Macdonald Gregor J; Steckler Thomas; Mackie Claire; Bridges Thomas M; Daniels J Scott; Niswender Colleen M; Noetzel Meredith J; Jones Carrie K; Conn P Jeffrey; Lindsley Craig W; Stauffer Shaun R

来源：Bioorganic & Medicinal Chemistry Letters, 2015, 25(6): 1310-1317.

DOI：10.1016/j.bmcl.2015.01.038

• Positive allosteric modulator (PAM)
• Metabotropic glutamate receptor 5 (mGlu(5))
• Imidazopyrimidinone
• Dihydroimidazopyrimidinone
• Schizophrenia

We report the discovery and SAR of two novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as metabotropic glutamate receptor 5 (mGlu(5)) positive allosteric modulators (PAMs). Exploration of several structural features in the western and eastern part of the imidazopyrimidinone core and combinations thereof, revealed compound 4a as a mGlu(5) PAM with good in vitro potency and efficacy, acceptable drug metabolism and pharmacokinetic (DMPK) properties and in vivo efficacy in an amphetamine-based model of psychosis. However, the presence of CNS-mediated adverse effects in preclinical species precluded any further in vivo evaluation.

• 出版日期2015-3-15